Carotenoids are naturally occurring red, yellow, orange, and green pigments produced by plants and some types of fungi and bacteria. It is believed that these pigments help protect the organism from potentially damaging effects of oxygen and light. Carotenoid molecules typically possess a series of conjugated double bonds, and can be divided into two groups. The provitamin A family of carotenoids, which are synthesized by the body to vitamin A, includes α- and β-carotene, and β-cryptoxanthin. Carotenoids that are not precursors to vitamin A include lycopene, lutein, and zeaxanthin. Studies suggest carotenoids offer anti-carcinogenic and anti-atherogenic protection.
As a family, carotenoids generally exhibit poor water solubility and low absorption from the gastrointestinal tract. The Merck Index, the relevant portions of which are hereby incorporated by reference, classifies α- and β-carotene, and zeaxanthin as “practically insoluble in water,” while lutein (also known as xanthophyll) is “insoluble in water.” The PDR For Nutritional Supplements, the relevant portions of which are hereby incorporated by reference, states that lycopene is “insoluble in water.” As a result of their poor water solubility, carotenoids also exhibit low bioavailability. For example, a study by Diwadkar-Navsariwala et al. (2003), which is incorporated by reference, reported that human lycopene absorption is poor and relatively constant, ranging between 3.4 mg-6.4 mg, even for escalating lycopene doses ranging from 10 mg-120 mg. Thus, there exists the need to enhance the bioavailability of carotenoids.
In addition to poor solubility, carotenoids also exhibit poor stability. In particular, the conjugated double bond structure of carotenoids renders them particularly susceptible to oxidation and light-induced degradation. Formulation techniques such as the use of protective colloids or emulsification systems have been used to prevent carotenoid degradation, but these techniques typically result in low active loads and/or limit final dosage formulation flexibility.
Carotenoids are well known in the dietary supplement market, primarily in two dosage forms: softgels and tablets. Softgel dosage forms typically contain beeswax, lecithin, gelatin, edible oils, glycerin and/or other emulsification technology to enhance the solubility of the carotenoid. However, soft gel technology is a more labor- and cost-intensive process than capsule/tablet technologies. Furthermore, emulsified carotenoid compositions are not well-suited for formulating with non-emulsified ingredients. Tablet forms of the carotenoids typically contain excipients such as microcrystalline cellulose, croscarmellose sodium, titanium dioxide, silicon dioxide and magnesium stearate to assist tableting, which may not provide bioenhancement or stability of the carotenoid.
U.S. Pat. No. 5,968,251 discloses a process to produce carotenoid compositions whereby an organic, water-miscible solution is first prepared containing a carotenoid colloid, which is then transferred into an aqueous phase to remove the organic solvent, leaving a nanodispersed carotenoid phase.
U.S. Pat. No. 5,863,953 discloses a double dispersion system in which particles are stabilized by a protective colloid dispersed in edible oil as a dispersion medium.
It is desirable to produce solid compositions of carotenoids exhibiting enhanced solubility and/or bioavailability and/or stability compared to the crystalline form of the compound. By converting a substantial portion of a crystalline carotenoid to the amorphous state, the aqueous solubility and bioavailability are increased. Furthermore, by incorporating the carotenoid in a solid dispersion, it may be protected from oxidation or light induced degradation. In addition, carotenoids presented as an amorphous solid may facilitate manufacturing of the finished product and provide dosage forms that are substantially free of added lipids or oils or that may contain other active ingredients.
Accordingly, certain embodiments of the present invention provide one or more of the following benefits:                1. Enhanced solubility and bioavailability of carotenoids;        2. Enhanced stability of carotenoids;        3. An enhanced form of carotenoids that does not require the use of oils, gelatins, or emulsification technology to allow for the preparation of capsules/tablets;        4. Increased flexibility in formulation and final product performance (i.e., release rate, powder compactability, multiple actives);        5. A more cost-effective method for providing this enhancement than technologies currently employed for preparing bioenhanced or stabilized carotenoids (e.g., softgel capsules, colloidal dispersions, emulsification technologies).        
Thus, in accordance with certain embodiments, the present invention relates to compositions of stable and/or bioenhanced carotenoids and methods for producing them. More particularly, certain aspects of the present invention relate to compositions and methods for preparing stable and/or bioenhanced carotenoids utilizing at least one solubility-enhancing organic material. In a preferred embodiment of the invention, the solubility-enhancing organic material is a polymer. In accordance with certain embodiments, the carotenoid is a provitamin A carotenoid (e.g., α-carotene, β-carotene, or β-cryptoxanthin) or a non-provitamin A carotenoid (e.g., lycopene, lutein, or zeaxanthin). Mixtures of carotenoids or a carotenoid with other actives are within the scope of the invention.
In one embodiment, the mixture is prepared by dry blending the carotenoid with a solubility-enhancing polymer. In another embodiment, the carotenoid is dissolved in a solvent containing the polymer. In yet another embodiment, a blend of solvent/non-solvent for the polymer is employed. The stable and/or bioenhanced carotenoid product is produced by any method suitable to the composition. In one embodiment, direct compression of physically blended carotenoid(s)-polymer(s) is used. When necessary, solvent can be removed from compositions to yield the stable and/or bioenhanced carotenoid product. In one further development of the invention, a carotenoid-polymer-solvent (or a solvent/non-solvent blend) solution or dispersion is spray dried to produce the carotenoid in a form that exhibits improved stability, solubility and/or bioavailability. The stable and/or bioenhanced carotenoid composition can be prepared by methods other than spray drying as recognized by those skilled in the art. Those methods include, without limitation: melt extrusion, spray congealing, and freeze drying. In accordance with particular embodiments of the invention, a significant portion of the carotenoid is provided in the amorphous state. In accordance with certain embodiments, the carotenoid is converted almost entirely to the amorphous state. In one embodiment of the invention, the carotenoid is converted to the completely amorphous state.